tbuckley/cabot-search huggingface dataset:
Enhancing Oral Performance of Paclitaxel Lipid‐Mimic Prodrug via Modulating Type of Fatty Acids
Authors: Yi‐fan Miao, Qing Ye, Ming‐yang Zhang, Lin Gao, Xi‐yan Wang, Wen‐xin Zhong, Zi‐xuan Wang, Zhong‐gui He, Chu‐tong Tian, Jin Sun
Journal: Advanced Healthcare Materials (2023)

Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.
Definitive liver radiotherapy for intrahepatic cholangiocarcinoma with extrahepatic metastases
Authors: Brian De, Rituraj Upadhyay, Kaiping Liao, Tiffany Kumala, Christopher Shi, Grace Dodoo, Joseph Abi Jaoude, Kelsey L. Corrigan, Gohar S. Manzar, Kathryn E. Marqueen, Vincent Bernard, Sunyoung S Lee, Kanwal P.S. Raghav, Jean-Nicolas Vauthey, Ching-Wei Tzeng, Hop S. Tran Cao, Grace Lee, Jennifer Wo, Theodore S Hong, Christopher H Crane, Bruce D. Minsky, Grace L. Smith, Emma B. Holliday, Cullen M. Taniguchi, Albert C. Koong, Prajnan Das, Milind Javle, Ethan B. Ludmir, Eugene Koay
Journal: Liver Cancer (2023)

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5–97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8–11) and 21 months (CI: 17–26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p &amp;lt; 0.001). Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.
IMiD Resistance in Multiple Myeloma: Current Understanding of the Underpinning Biology and Clinical Impact
Authors: Sarah Anne Bird, Charlotte Pawlyn
Journal: Blood (2023)

Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease and are approved as a single agent maintenance treatment after autologous stem cell transplantation. However patients will become resistant to ongoing therapy over time and inevitably relapse. It is only in the last decade that the mechanism of IMiD action has been elucidated; through binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase a set of neosubstrates is designated for degradation by the proteosome. In myeloma cells this includes the zinc-finger B cell transcription factors Ikaros and Aiolos which in turn leads to decreased levels of IFR4 and c-MYC and cell death. As our knowledge of IMiD mechanism of action has advanced, the ability to study resistance mechanisms has also developed. This review will explore the existing work on IMiD resistance and propose areas of future research that may advance our understanding and management of this common clinical condition.
Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in Von Willebrand disease murine models
Authors: Stéphanie Roullet, Norman Luc, Julie Rayes, Jean Solarz, Dante Disharoon, Andrew J Ditto, Emily Gahagan, Christa Pawlowski, Thibaud Sefiane, Frédéric Adam, Caterina Casari, Olivier D. Christophe, Michael A Bruckman, Peter J Lenting, Anirban Sen Gupta, Cecile V Denis
Journal: Blood (2023)
CRISPR/Cas9-mediated <i>Cxcr4</i> Disease Allele Inactivation for Gene Therapy in a Mouse Model of WHIM Syndrome
Authors: Ji-Liang Gao, Albert Owusu-Ansah, Alexander Yang, Erin Yim, David H McDermott, Paejonette Jacobs, Shamik Majumdar, Uimook Choi, Colin L Sweeney, Harry L Malech, Philip M Murphy
Journal: Blood (2023)
Table of contents
Authors: Melika Motamedi, Giovanni Ferrara, Elaine Yacyshyn, Mohammed Osman, Andy Abril, Samia Rahman, Elena Netchiporouk, Robert Gniadecki, Lydia Ouchene, Anastasiya Muntyanu, Deborah Assayag, E Vicka Veilleux, Christian Pineau, Elizabeth O'brien, Murray Baron, Murad Alam, Nikki Levin, Jane Grant-Kels, Dirk Elston, Brett Sloan, Warren Heymann, Yi-Teng Hung, Yen-Wen Chen, Yenlin Huang, Yu-Jr Lin, Chun-Bing Chen, Wen-Hung Chung, Cimarron Sharon, Richard Straker, Phyllis Gimotty, Emily Chu, Tara Mitchell, John Miura, Michael Marchetti, Edmund Bartlett, Giorgos Karakousis, Perrine Rousset, ´phane Dalle, Laurent Mortier, Olivier Dereure, Sophie Dalac, Caroline Dutriaux, Marie -The ´re `se Leccia, Delphine Legoupil, Florence Brunet-Possenti, Julie De Quatrebarbes, Jean-Jacques Grob, Philippe Saiag, Eve Maubec, Pierre-Emmanuel Stoebner, Florence Granel-Brocard, Jean-Philippe Arnault, Clara Allayous, Bastien Oriano, ´leste Lebbe, Henri Montaudie, Lisa Beck, Thomas Bieber, Stephan Weidinger, Marie Tauber, Hidehisa Saeki, Alan Irvine, Lawrence Eichenfield, Thomas Werfel, Petra Arlert, Li Jiang, Mads Røpke, Amy Paller, Khalaf Kridin, Ralf Ludwig, Katherine Wojcik, Makenzie Hawkins, Amy Anderson-Mellies, Evan Hall, Ashley Wysong, Joel Milam, Ann Hamilton, Myles Cockburn, Matthew Taylor, David Margolis, Shawn Kwatra, John Barbieri, Mari Wataya-Kaneda, Yoshiyuki Watanabe, Ayumi Nakamura, Kouji Yamamoto, Kiyoshi Okada, Shinichiro Maeda, Keisuke Nimura, Kotaro Saga, Ichiro Katayama, Marissa Ceresnie, Lindsey Mohney, Dayoung Do, Henry Ko, Tasneem Lim, Quinn Willer, Jackson Bowers, Emily Baumrin, Jules Lipoff, Jennifer Fernandez, Sabrina Dahak, Melodi Whitley, Brandon Smith, Michael Collier, Shivali Devjani, George Han, Jashin Wu, Deborah Lin, Giselle Martins, Jessika Sanz, Ludmila Corral, Mariya Miteva, Julia Vanlerberghe, Fre ´de ´ric Dezoteux, Claire Martin, Marie Jachiet, Ange Le Soria, Florence Te ´tart, Anne-Be ´ne ´dicte Modeste-Duval, Anne-Claire Bursztejn, Laurent Misery, Audrey Lasek, Camille Leleu, ´lie Du-Thanh, Justine Pasteur, Pauline Pralong, Audrey Nosbaum, Catherine Droitcourt, Manuelle Viguier, Julien Seneschal, ´bastien Barbarot, Delphine Staumont-Salle
Journal: Journal of the American Academy of Dermatology (2023)
Iron homeostasis governs erythroid phenotype in Polycythemia Vera
Authors: Cavan Bennett, Victoria E Jackson, Anne Pettikiriarachchi, Thomas Hayman, Ute Schaeper, Gemma L Moir-Meyer, Katherine Louise Fielding, Ricardo Ataide, Danielle Clucas, Andrew James Baldi, Alexandra L Garnham, Connie SN Li-Wai-Suen, Stephen John Loughran, E Joanna Baxter, Anthony R Green, Warren S Alexander, Melanie Bahlo, Kate Burbury, Ashley P Ng, Sant-Rayn Pasricha
Journal: Blood (2023)

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
Characteristic Muscular FDG Uptake Patterns Related to the Transportation Means Used by Patients to Visit the Hospital
Authors: Chio Okuyama, Kuninori Kusano, Miki Ito, Akiko Takase, Sayaka Goda, Shinya Kagawa
Journal: Clinical Nuclear Medicine (2023)

It is well-known that physiological FDG uptake in the skeletal muscles is affected by serum insulin levels and the extent to which the muscles contract before the examination. Patients are instructed to refrain from strenuous exercise, talking too much, and taking meals at least 4 hours before the administration of the tracer. Even if the patient does not intend to exercise, muscular accumulation related to specific behaviors can still be visualized in the images. In this manuscript, we present FDG PET/CT images from 4 cases reflecting the mode of transportation used by the patients to visit the hospital.
JAAD Case Reports article list
Authors: Larissa Lobo, Francisco Mateus, Joa ˜o, Maria Zeli, Moreira Frota, Monica Santos, Doniya Milani, Alejandro Rabionet, Paul Rodriguez-Waitkus, Ann Lin, Wei-Shen Chen, Travis Dowdle, Jeannie Nguyen, Ashley Sturgeon, Michelle Tarbox, Cloyce Stetson, Mohammad Fardos, Daniel Hogan, Aref Moshayedi, Rachel Lee, Lauren Tisdale, Jennifer Crimmins, Bailey Alkhatib, Hesham Alshaikh, Heather O'connor, Dirk Elston, Kristin Petit, Elizabeth Rogozinski, Julian Trevino, Ramesh Bhat, Jyothi Jayaraman, Monisha Madhumita, Elise Toulemonde, Marion Douxami, Sarah Faiz, Romain Dubois, Marie Verhasselt-Crinquette, Olivier Carpentier, Henry Abi Rached, Laurent Mortier, Talimogene Laherparepvec, Erin Mcclure, Neha Singh, Kim Abson, Shailender Bhatia, Heidi Gray, Laura Brown, Ata Moshiri, Sophia Ba, Jamison Harvey, David Swanson, Annika Belzer, Vignesh Ramachandran, Shane Meehan, Miriam Pomeranz, Marina Matatova, Meryl Musicante, Yamila Goenaga-Va ´zquez, Natasha Klimas, Mary Mcdaniel, H Nicholas Shamma, Jaclyn Wetli, Scott Mcgaugh, Teja Chakrala, Roshni Prakash, Kiran Motaparthi, Neda Shahriari, Daniel Mazori, Joseph Merola, Leah Swanson, Freyr Johannsson, Silvia Tortorelli, Cecilia Yi, Surbhi Shah, Raymond Zhao, Taylor Novice, Sasank Konda, Camilla Cascardo, Georgeanne Cornell, John Moesch, Aaron Tisack, Marc Vliet, David Ozog, Teresa Xiao, Ekene Ezenwa, Arlene Ruiz De Luzuriaga, Mark Hoffman, Changhua Zhu, Jie Fok, Lihang Lin, Huichun Su, Marcus Maurer, Efrat Bar-Ilan, Jacob Mashiah, Liran Horev, Yizhak Confino, Andrea Ga ´l, Zsuzsanna Szalai, Elisa Gallo, Aviv Barzilai, Shoshana Greenberger, Ayelet Ollech, Elif Karatas, Ali Nazim, Parth Patel, Toral Vaidya, George Drew, Sanober Amin, Ashley Keyes, Maira Fonseca, Adnan Mir, Caroline Halverstam, Anna Davis, Brielle Raine, Isaac Swartzman, Paul Bogner, Michael Nazareth, Catherine Hobayan, Catherine Chung, Manar Edriss, Jennifer Parker, Ellen Pritchett
Journal: Journal of the American Academy of Dermatology (2023)
Activation of Hippo Pathway Damages Slit Diaphragm by Deprivation of Ajuba Proteins
Authors: Kevin Gilhaus, Claudia Cepok, David Kamm, Beate Surmann, Pavel I. Nedvetsky, Jana Emich, Alina Sundukova, Katharina Saatkamp, Harald Nüsse, Jürgen Klingauf, Dirk O. Wennmann, Britta George, Michael P. Krahn, Hermann-Joseph Pavenstädt, Beate A. Vollenbröker
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Nuclear exclusion of the cotranscription factor YAP, which is a consequence of activation of the Hippo signaling pathway, leads to FSGS and podocyte apoptosis. Ajuba proteins play an important role in the glomerular filtration barrier by keeping the Hippo pathway inactive. In nephrocytes from Drosophila melanogaster , a well-established model system for podocyte research, Ajuba proteins ensure slit diaphragm (SD) formation and function. Hippo pathway activation leads to mislocalization of Ajuba proteins, decreased SD formation, rearrangement of the actin cytoskeleton, and increased SD permeability. Targeting the kinases of the Hippo pathway with specific inhibitors in the glomerulus could, therefore, be a promising strategy for therapy of FSGS. Background The highly conserved Hippo pathway, which regulates organ growth and cell proliferation by inhibiting transcriptional cofactors YAP/TAZ, plays a special role in podocytes, where activation of the pathway leads to apoptosis. The Ajuba family proteins (Ajuba, LIM domain-containing protein 1 (LIMD1) and Wilms tumor protein 1–interacting protein [WTIP]) can bind and inactivate large tumor suppressor kinases 1 and 2, (LATS1/2) two of the Hippo pathway key kinases. WTIP, furthermore, connects the slit diaphragm (SD), the specialized cell-cell junction between podocytes, with the actin cytoskeleton. Methods We used garland cell nephrocytes of Drosophila melanogaster to monitor the role of Ajuba proteins in Hippo pathway regulation and structural integrity of the SD. Microscopy and functional assays analyzed the interplay between Ajuba proteins and LATS2 regarding expression, localization, interaction, and effects on the functionality of the SD. Results In nephrocytes, the Ajuba homolog Djub recruited Warts (LATS2 homolog) to the SD. Knockdown of Djub activated the Hippo pathway. Reciprocally, Hippo activation reduced the Djub level. Both Djub knockdown and Hippo activation led to morphological changes in the SD, rearrangement of the cortical actin cytoskeleton, and increased SD permeability. Knockdown of Warts or overexpression of constitutively active Yki prevented these effects. In podocytes, Hippo pathway activation or knockdown of YAP also decreased the level of Ajuba proteins. Conclusions Ajuba proteins regulate the structure and function of the SD in nephrocytes, connecting the SD protein complex to the actin cytoskeleton and maintaining the Hippo pathway in an inactive state. Hippo pathway activation directly influencing Djub expression suggests a self-amplifying feedback mechanism.
Advanced Nanomedicine: Redefining Therapeutic Paradigms for Inflammatory Bowel Disease
Authors: Yinfeng Zhang, Tingting Wang, Meng Sun, Yueyue Song, Xinyuan Huang, Shutian Zhang, Jun Yang, Jinfeng Zhang
Journal: Advanced Healthcare Materials (2023)

Abstract Inflammatory bowel disease (IBD), a chronic and recurrent gastrointestinal inflammatory disorder with a variety of painful clinical manifestations and an increased risk of cancerization or death, has become an emerging challenge to global healthcare due to its rapidly increasing incidence. At present, there is no efficient cure against IBD because of the elusive etiology and pathogenesis of IBD. Therefore, the development of alternative therapeutic strategies with positive clinical efficacy and reduced side effects is urgently needed. In recent years, the great prosperity of nanomedicine promoted by a variety of advanced nanomaterials is redefining more attractive and promising therapeutic strategies for IBD owing to their advantages in the physiological stability, bioavailability, and targeting of inflammatory sites. In this review, firstly the basic characteristics of healthy and inflammatory intestinal microenvironments are presented. Then, different administration routes and targeting strategies of nanotherapeutics for IBD treatment are reviewed. Subsequently, a specific focus is placed on the introduction of nanotherapeutic treatments based on different IBD pathogenesis. Finally, some future challenges and perspectives of the currently developed nanomedicines for IBD treatment are provided. It is believed that the above topics will attract researchers from various fields including medicine, biological sciences, materials, chemistry and pharmaceutics.
Genetic association analysis of 77,539 genomes reveals rare disease etiologies
Authors: Daniel Greene, Daniela Pirri, Karen Frudd, Ege Sackey, Mohammed Al-Owain, Arnaud P. J. Giese, Khushnooda Ramzan, Sehar Riaz, Itaru Yamanaka, Nele Boeckx, Chantal Thys, Bruce D. Gelb, Paul Brennan, Verity Hartill, Julie Harvengt, Tomoki Kosho, Sahar Mansour, Mitsuo Masuno, Takako Ohata, Helen Stewart, Khalid Taibah, Claire L. S. Turner, Faiqa Imtiaz, Saima Riazuddin, Takayuki Morisaki, Pia Ostergaard, Bart L. Loeys, Hiroko Morisaki, Zubair M. Ahmed, Graeme M. Birdsey, Kathleen Freson, Andrew Mumford, Ernest Turro
Journal: Nature Medicine (2023)

Abstract The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG , PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.
Platelets at the Vessel Wall in Non-Thrombotic Disease
Authors: Anu Aggarwal, Courtney L. Jennings, Emily Manning, Scott J. Cameron
Journal: Circulation Research (2023)

Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.
Pneumonia-Induced Inflammation, Resolution and Cardiovascular Disease: Causes, Consequences and Clinical Opportunities
Authors: Cameron Stotts, Vicente F. Corrales-Medina, Katey J. Rayner
Journal: Circulation Research (2023)

Pneumonia is inflammation in the lungs, which is usually caused by an infection. The symptoms of pneumonia can vary from mild to life-threatening, where severe illness is often observed in vulnerable populations like children, older adults, and those with preexisting health conditions. Vaccines have greatly reduced the burden of some of the most common causes of pneumonia, and the use of antimicrobials has greatly improved the survival to this infection. However, pneumonia survivors do not return to their preinfection health trajectories but instead experience an accelerated health decline with an increased risk of cardiovascular disease. The mechanisms of this association are not well understood, but a persistent dysregulated inflammatory response post-pneumonia appears to play a central role. It is proposed that the inflammatory response during pneumonia is left unregulated and exacerbates atherosclerotic vascular disease, which ultimately leads to adverse cardiac events such as myocardial infarction. For this reason, there is a need to better understand the inflammatory cross talk between the lungs and the heart during and after pneumonia to develop therapeutics that focus on preventing pneumonia-associated cardiovascular events. This review will provide an overview of the known mechanisms of inflammation triggered during pneumonia and their relevance to the increased cardiovascular risk that follows this infection. We will also discuss opportunities for new clinical approaches leveraging strategies to promote inflammatory resolution pathways as a novel therapeutic target to reduce the risk of cardiac events post-pneumonia.